Abstract

Multiple sclerosis (MS) is an autoimmune and demyelinating disease of the central nervous system characterised by incoordination, sensory loss, weakness, changes in bladder capacity and bowel function, fatigue and cognitive impairment, creating a significant socioeconomic burden. The pathogenesis of MS involves both genetic susceptibility and exposure to distinct environmental risk factors. The gene x environment interaction is regulated by epigenetic mechanisms. Epigenetics refers to a complex system that modifies gene expression without altering the DNA sequence. The most studied epigenetic mechanism is DNA methylation. This epigenetic mark participates in distinct MS pathophysiological processes, including blood-brain barrier breakdown, inflammatory response, demyelination, remyelination failure and neurodegeneration. In this study, we also accurately summarised a list of environmental factors involved in the MS pathogenesis and its clinical course. A literature search was conducted using MEDLINE through PubMED and Scopus. In conclusion, an exhaustive study of DNA methylation might contribute towards new pharmacological interventions in MS by use of epigenetic drugs.

Conflict of interest statement

Figures

The underlying pathophysiological mechanism of MS. In the first instance, autoreactive CD4+ T…

Fig. 1

The underlying pathophysiological mechanism of MS. In the first instance, autoreactive CD4+ T cells are activated in the periphery by antigen presenting cells (APC) that present, in conjunction with class II MHC molecules, similar antigens to those synthesised by the CNS. (1) This interaction activates the differentiation of CD4+ T naïve cells into CD4+ T helper cells (Th). (2) Upon activation, Th produces interferon-gamma (IFN-γ), a cytokine responsible for recruiting CD8+ T cells, B cells and monocytes in the periphery. (3) These proinflammatory cells migrate to the blood–brain barrier (BBB) and pass into the CNS. Inside the brain, plasma B cells produce auto-antibodies against CNS self-antigens contributing to myelin sheath damage. This process is aggravated when infiltrated cytotoxic CD8+ T cells attack oligodendrocytes causing their destruction and neuronal death. Monocytes, on the other hand, increase local inflammatory response by releasing proinflammatory cytokines and contributing to demyelination through myelin phagocytosis. (4) In parallel, infiltrated CD4+ T cells are reactivated upon interaction with myelin fragments presented by resident APCs which favours (5) proinflammatory cytokines and chemokines release, (6) astrogliosis and microgliosis

Fig. 2

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DNA methylation metabolism. The addition…

Fig. 2

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DNA methylation metabolism. The addition of a methyl group to a naked cytosine…

Fig. 2

DNA methylation metabolism. The addition of a methyl group to a naked cytosine is catalysed by DNMT (black arrow). 5-methylcytosine (5mC) is oxidised by TET enzymes to 5-hydroxymethylcytosine (5hmC) which can be further oxidised to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) as indicated red arrows. In the deamination pathway (green arrows), AID or APOBEC can deaminate 5hmC to 5-hydroxymethyluracil (5hmU) or 5mC to thymine. Eventually, all these modified bases (5hmU, Thymine, 5fC, 5caC) are recognised by TDG and converted to naked cytosine through the base excision repair (BER) pathway (blue arrows)

Fig. 3

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Risk factors of multiple sclerosis.…

Fig. 3

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Risk factors of multiple sclerosis. MS pathogenesis is influenced by both genetic and…

Fig. 3

Risk factors of multiple sclerosis. MS pathogenesis is influenced by both genetic and environmental factors. Among the genetic factors, gender, disease-modifier genes, disease susceptibility genes and single nucleotide polymorphisms are remarkably important in prevalence and MS pathogenesis. In contrast, environmental factors such as smoking, vitamin D deficiency, organic solvents and pollutants exposure, diet style, Epstein Barr infection, dysbiosis of the gut microbiota, lack of exercise and stress are critically associated with MS susceptibility and progression